Autologous hematopoietic cell transplantation

What every physician needs to know about autologous hematopoietic cell transplantation

Autologous hematopoietic cell transplantation (HCT) is the intravenous infusion of hematopoietic stem and progenitor cells designed to re-establish marrow and immune function in patients with a variety of acquired malignant disorders, who are being treated with high dose chemotherapy or chemoradiotherapy to treat the disease. These include hematologic malignancies (for example, Hodgkin's lymphoma, B and T cell lymphoma and multiple myeloma).

HCT also is used in the support of patients undergoing high-dose chemotherapy for the treatment of certain solid tumors for whom hematologic toxicity would otherwise limit drug administration (germ cell, soft-tissue sarcomas, and neuroblastoma).

With the recognition that the marrow stem cells circulate in the peripheral blood, growth factor based methods have been devised to augment the number of these cells in the patient's circulation, especially following recovery from chemotherapy such as cyclophosphamide. The blood is then collected on a cell separator and frozen in a DMSO (dimethyl sulfoxide) ,to be used after high-dose chemotherapy and/or radiation therapy. This is now the most common source of stem cells used in the autologous setting.

Advantages and disadvantages of autologous stem cell transplantation

In autologous transplantation, the reinfused stem cells are derived from the patient's own bone marrow and collected from the peripheral blood. These cells do not cause graft-versus-host disease (GVHD), and thus, autologous transplantation is associated with less morbidity and mortality than is allogeneic bone marrow transplant (BMT) and increases the age limit and the number of patients who can undergo the procedure.

The disadvantages of autologous BMT include the likelihood of tumor cell contamination within the graft in many diseases, which can contribute to relapse; the lack of a significant therapeutic graft-versus-tumor effect; and the limited ability to use autologous stem cells to treat patients not in remission or with inherited nonmalignant lympho-hematopoietic diseases (Table I).

Table I

Comparison of allogeneic versus autologous stem cell transplantation

Advantages

Disadvantages

Allogeneic

No tumor contamination of the graft and no prior marrow injury from chemotherapy (less risk of later myelodysplasia)

Dose intensive regimen limited by toxicity (usually limited to patients up to the age of 55 years)

Graft-versus-tumor effect

Time needed to identify donor if no sibling donor available / limited availability of donor for some ethnic groups

Can be used for patients with marrow involvement by tumor or with bone marrow dysfunction, such as aplastic anemia, hemoglobinopathies, or prior pelvic irradiation

Higher early treatment related mortality from GVHD and infectious complications (20-40%) depending upon age and donor source

Autologous

No need to identify donor if peripheral blood marrow is uninvolved by tumor at the time of collection

Not feasible if peripheral blood stem cells/marrow involved

No immunosuppression = less risk of infections

Possible marrow injury leading to late myelodysplasia (either from prior chemotherapy or transplant regimen)

No GVHD

No graft-versus-tumor effect

Dose intensive therapy can be used for older patients (usually up to age 70)

Not all patients can be mobilized to give adequate cell doses for reconstitution

Low early treatment related mortality

What features of the presentation will guide me toward possible causes and next treatment steps:

The issue for any patient is whether treatment with autologous transplantation will improve the chances of cure and whether an autologous or allogeneic transplant should be the therapy used to accomplish this.

What laboratory studies should you order to help make the diagnosis and how should you interpret the results?

Collection of the autologous graft

Collection of circulating peripheral blood progenitor cells is performed via an apheresis technique. Although this procedure can be accomplished in an individual with a baseline blood count, the number of cells and the efficiency of collection are increased if the cells are procured during white blood cell (WBC) recovery following chemotherapy or after the administration of hematopoietic growth factors.

The most effective strategy appears to be the collection of cells after the administration of both chemotherapy and growth factors. In most circumstances, adequate numbers of cells can be collected using granulocyte colony-stimulating factor (G-CSF, filgrastim [Neupogen]) to prime the patient prior to one to three apheresis procedures. In particular, in patients for whom this is not successful, the use of plerixafor (Mozobil) may be effective.

Currently, the adequacy of the number of hematopoietic stem cells is assessed by determining the number of cells that have the CD34 antigen (stem cell) marker. Usually, a minimum of 2 × 106 CD34 cells/kg of body weight is required to ensure engraftment.

How to decide about transplant indication and type of transplant

What are the clinical situations where autologous transplantation should be considered (auto versus allo)?

The expanded number of stem cell sources for stem cell transplantation have complicated transplantation choices for patients and their physicians. Therefore, the decision requires evaluation of the patient and the disease involved.

The most common use of allogeneic HCT has been for the eradication of hematologic malignancies, such as acute leukemia, myelodysplasia and non-Hodgkin lymphoma, but is associated with significant toxicity and mortality risks. Thus, the important principle is to consider the prognosis of the patient if HCT is not performed and assess if the benefit of HCT (reduction in relapse) significantly outweighs its toxicity and upfront mortality risks and whether to perform an allogeneic or autologous transplant to accomplish this goal.

Acute myeloid leukemia

Based on the current data, patients who are unlikely to be cured with conventional chemotherapy alone should be considered for allogeneic HCT rather than autologous transplant. These include especially patients who are beyond first complete remission (CR), that is, induction failure or relapse with 2nd or subsequent CR for whom autologous transplant is not effective.

In general, if the possibility of cure for a given patient is estimated to be 30-40% or less, one could justify the use of allogeneic HCT despite its non-relapse mortality rate of 20-30%. Thus high-risk patients (that is, high-risk chromosome abnormalities [that is, -7, -5, complex abnormalities], therapy-related acute myeloid leukemia (AML), transformed AML from prior myelodysplastic syndrome (MDS), high WBC counts at presentation) should be considered for allogeneic HCT. Autologous HCT has not been very successful in these patients due to a lack of a graft-versus-tumor effect and the persistence of abnormal cells in the graft.

Low-risk patients in first CR (that is, good risk cytogenetic abnormalities) are not generally considered for allogeneic or autologous HCT. New molecular markers improved the decision-making process for AML patients with normal cytogenetics (intermediate risk). Normal cytogenetics AML with Flt-3 mutation are considered as allogeneic HCT candidates, whereas those without Flt-3 mutation but with NPM-1 mutation are at good risk and not considered for allogeneic HCT.

Proto-oncogene c-kit mutation also identifies a high-risk group within good risk cytogenetic abnormalities (core-binding factor AML) of t(8;21) and inv(16). These molecular markers are increasingly important to be tested at presentation of AML. The one clinical setting where auto transplant can be used effectively in AML is patients with acute promyelocytic leukemia in second complete remission, especially if in a polymerase chain reaction negative remission. If this cannot be achieved, then an allogeneic transplant would be a preferable approach.

Acute lymphocytic leukemia

As in AML, allogeneic HCT is considered the only curative option for patients in second CR acute lymphocytic leukemia (ALL). In addition, it is the best therapy to reduce the chances of relapse for patients with ALL in first remission. These include Philadelphia chromosome, WBC counts greater than 30,000/µl (B lineage) or greater than 50,000/µl (T lineage), hypodiploidy, or MLL gene rearrangement. Autologous HCT is not considered effective for this disease in any of these clinical settings.

Other hematologic malignant diseases

Currently, there is no role for autologous transplant for MDS, chronic myelogenous leukemia, chromic lymphoid leukemia or myelofibrosis and allogeneic transplant is the preferred therapy when transplant is indicated.

Non-Hodgkin lymphoma

Autologous HCT is the treatment of choice for relapsed / refractory diffuse large B cell non-Hodgkins lymphoma (NHL) which is chemosensitive to salvage therapy, usually with a regimen different to what they received for primary therapy.

With the improved outcomes incorporating rituximab in first-line regimens, autologous HCT as consolidation for first CR patients with diffuse large B cell NHL have not been clearly proven beneficial by randomized trials, although recent data suggests that auto transplant in first remission reduces relapse in patients with high risk disease.

Autologous HCT is not recommended for patients who have had multiple relapses. Thus, for patients with a first relapse of B cell lymphoma, the usual strategy is to treat with two to three cycles of chemotherapy, followed by scans of the responsiveness of the lymphoma to the salvage chemotherapy, collection of stem cells upon recovery and then high dose chemotherapy and stem cell transplant.

The prognosis after transplant is related to the length of the first remission, responsiveness to salvage chemotherapy, the extent of disease at the time of relapse and the depth of the response to treatment (PET negative versus PET positive).

For mantle cell lymphoma, autologous HCT is considered for patients in first CR after achievement of remission. Autologous HCT has shown to prolong overall survival (OS) and progression-free survival (PFS) for relapsed / refractory follicular NHL, although it is not considered curative, except in patients in a second remission (not multiply relapsed). Increasingly, allogeneic transplant, due to the strong allogeneic response against low grade lymphoma, is utilized for patients with this form of lymphoma with a high rate of cure, especially those who have progressed after multiple different types of chemotherapy.

Allogeneic HCT can also be considered for relapsed / induction failure intermediate-high grade NHL, who could not proceed with auto-HCT due to bone marrow involvement of lymphoma / failure to collect sufficient number of CD34+ hematopoietic progenitor cells. NHL patients who relapse after prior autologous HCT can be considered for allogeneic HCT using reduced-intensity conditioning. NHL patients who develop secondary MDS are clearly candidates for allogeneic HCT. Selected cases of relapsed low-grade NHL can also be considered for allogeneic HCT (that is, multiple relapse, 1st relapse with high-risk features, relapse after autologous HCT).

Patients with T cell lymphoma (anaplastic large cell, anaplastic lymphoma kinase negative), peripheral T cell lymphoma and angioimmunoblastic lymphoma may also benefit from autologous transplant after primary treatment, when in first remission. Once relapse occurs, an allogeneic transplant can still cure approximately 40% of such patients.

Hodgkin lymphoma

There is currently no role for autologous transplant for patients with newly diagnosed Hodgkin disease who achieve a remission with standard up front chemotherapy. It is, however, the most effective curative treatment for patients who have suffered a first relapse after front line chemotherapy, using the same principles as applied to the patient with relapsed large B cell lymphoma.

Studies by the British National Lymphoma Investigation and the GHSD / European Bone Marrow Transplant group demonstrated improved PFS / event-free survival (but not OS) with autologous HCT, compared with conventional chemotherapy in relapsed or refractory Hodgkin lymphoma. Reduced-intensity allogeneic HCT can be considered for HL patients who relapse after autologous HCT.

Multiple myeloma

Autologous HCT is associated with high response rates and remains the preferred approach for multiple myeloma (MM), after initial induction therapy. Its benefit over conventional cytotoxic chemotherapy has been demonstrated in multiple randomized studies. While most of these studies enrolled patients less than 65years old, recent studies suggest benefits in older patients.

Tandem autologous HCT has been associated with improved EFS and OS. However, the added benefit was not seen in a subset of patients with a CR or very good partial response. A delayed second autologous HCT can be beneficial for selected cases of myeloma patients relapsed after the first HCT.

It should also be noted that these randomized studies were designed prior to the availability of thalidomide, Revlimid, or bortezomib. Therefore, the role of autologous HCT may evolve and be refined in the future. Autologous HCT is not considered curative for MM and recent efforts include post-HCT maintenance therapy to delay future recurrences. An approach of combined auto-HCT followed by non-myeloablative HCT showed a promising result in phase II studies, yet the results from phase III trials showed mixed data without clear advantage in this approach. Thus upfront allogeneic HCT is only recommended in the context of clinical trials.

Solid tumors

In general, autologous transplantation is used for selected solid tumors, such as germ-cell, soft-tissue sarcomas, and neuroblastoma.

When do you need to get more aggressive tests:

What are the laboratory and radiological tests to be performed prior to autologous transplant?

All patients require testing to determine disease status / burden before transplant, as well as assessment of organ function (heart, pulmonary, renal, liver, psychosocial), and an infectious disease evaluation for viruses such as hepatitis B and C and HIV. In addition, it is strongly recommended that patients have cytogenetic analysis of the marrow before collection of stem cells, to reduce the risk of MDS; patients with cytogenetic abnormalities at the time of stem cell collection, are at very high risk for developing MDS and should be considered for allogeneic transplant.

What imaging studies (if any) will be helpful?

Imaging studies are required to assess extent of disease and the response to treatment, particularly in evaluating patients with lymphoma and Hodgkin lymphoma. These tests are also used to assess any evidence of lingering or complicating infections (lung, liver) prior to high dose chemotherapy.

What therapies should you initiate immediately and under what circumstances - even if root cause is not identified?

What are the phases of an autologous transplant after collection of stem cells?

In the first phase of marrow transplantation, the preparative phase, patients receive high-dose chemotherapy and / or radiation therapy (sometimes referred to as a conditioning regimen).

For patients undergoing autologous transplantation, stem cells are reinfused following high-dose therapy, to reestablish hematopoiesis as rapidly as possible. The regimens used for autologous BMT depend upon the disease being treated. High-dose melphalan (Alkeran; 200mg/m²) is the most commonly used regimen for myeloma, and BEAM (BiCNU [Carmustine], etoposide, cytarabine [Ara-C], and melphalan) or CBV (cyclophosphamide, BiCNU [Carmustine] and etoposide [Vepesid]) are the two most commonly used regimens for lymphoma.

Although some programs still utilize a total body irradiation approach (1,200 rads total dose), combined with chemotherapy, most programs and trials use a chemotherapy based regimen. Recent trials have incorporated radioimmunotherapy into the high-dose chemotherapy regimens in the treatment of B-cell lymphoma (Bexxar, Zevalin), but randomized trials have not yet shown an advantage to this approach.

What are the toxicities of preparative regimens used for transplantation?

The acute toxicities of irradiation and chemotherapy include nausea and vomiting, which can be managed by prophylactic use of antiemetics, particularly serotonin antagonists. Busulfan can cause seizures; prophylactic phenytoin is effective in preventing this complication. Both cyclophosphamide and etoposide require forced hydration to reduce toxicities. Table II lists the acute and long-term toxicities of the major agents used in bone marrow transplantation preparative regimens.

Transplant phase of cryopreserved autologous stem cells

After completion of the preparative regimen, there is a day or more wait before reinfusion of peripheral blood stem cells. This delay allows for elimination of any active drug metabolites so that the reinfused cells are not injured by any remaining drug.

Minimal toxicities are associated with the infusion. They include headache, nausea, and dizziness. This dizziness is related more to the cryoprotectant dimethyl sulfoxide used to store cells from most patients undergoing autologous transplantation, than to the infusion.

Table II

Acute and long-term toxicities of common preparative agents used for HCT

What other therapies are helpful for reducing complications?

Supportive care phase

Following administration of the preparative regimen and during and after marrow transplantation, all patients require strict attention to infectious disease related complications, secondary to neutropenia. The duration of neutropenia following transplantation increases the risk of complicating infections.

Patients undergoing full allogeneic transplantation usually require more stringent isolation, whereas patients undergoing autologous transplantation need less rigorous protection. With the availability of more effective antiemetics, portions of the transplantation can now be performed in the outpatient setting, especially in patients with myeloma.

Neutropenic phase

Nearly all patients undergoing transplantation will develop fever, often with positive blood cultures, within 7 days of becoming neutropenic. Sepsis usually is caused by enteric bacteria or those found on the skin, and antibiotic choices are based on initial assessment and the results of blood cultures. The antibiotics chosen are continued until the neutrophil count begins to rise (greater than 500k/µL).

Prevention of fungal infections

For patients who are expected to have prolonged neutropenia, various methods of antifungal prophylaxis are used, including oral fluconazole (Diflucan; 200mg bid) or voriconazole (Vfend; 200mg IV or PO bid). The use of liposomal amphotericin B (AmBisome, Abelcet) or caspofungin (Cancidas) formulations has improved the safety and lowered the toxicity of antifungal therapy and is particularly worthwhile in patients with renal compromise.

Mucositis, nausea and anorexia

Regimen related toxicity often results in severe oral mucositis, nausea, and anorexia. Patients often require supplemental parenteral nutrition to maintain adequate caloric intake during this period. Because of the mucositis, enteral feedings are usually not employed, and total parenteral nutrition is maintained until patients are able to eat.

Studies are exploring novel agents that could prevent severe mucositis or accelerate healing, with recombinant keratinocyte growth factor (palifermin), which has been shown to decrease this complication, following total body irradiation based autologous transplant regimens.

Oral herpes simplex virus reactivation

Nearly all patients who are seropositive for herpes simplex virus (HSV) will have a reactivation of the virus, which can accentuate the pain and oral discomfort following BMT. To prevent this problem, most transplant programs use acyclovir at a dose of 250mg/m² tid during the neutropenic phase.

What is engraftment syndrome and how should it be managed?

This is a poorly understood syndrome of fever, skin rash, pulmonary infiltrates, cough and shortness of breath occurring just prior to, or at the time of the rise in the white cell count. It is best managed by the use of corticosteroids, while at the same time evaluating the patient for any infectious causes of the fever. The symptoms usually respond rapidly to treatment and the medication can be tapered over a few days, to weeks.

Transfusion support

All patients will require both red blood cells and platelets in proportion to the duration of the pancytopenia. Platelet levels are kept over 10,000 to 15,000 because of complicating bleeding from mucositis, although, in some instances, a lower threshold is feasible. Patients no longer receive granulocyte transfusions unless they have uncontrolled sepsis with positive blood cultures.

All blood products are irradiated to prevent engraftment of lymphoid cells and are often filtered, to reduce Cytomegalovirus (CMV) or alloimmunization and febrile reactions. Most patients receive single donor platelet pheresis products, which may need to be human leukocyte antigen matched if patients show evidence of refractoriness to the transfusion (that is, if platelet levels fail to rise after transfusion).

What are the late infections that occur after autologous transplant and how can they be prevented?

Late infections after BMT are caused by impaired cellular and humoral immunity. The most common late pathogens include Pneumocystis carinii pneumonia, varicella zoster virus, and encapsulated bacteria.

P. carinii prophylaxis

All patients undergoing transplantation require prophylaxis against P. carinii infection. This can be accomplished with one double-strength trimethoprim-sulfamethoxazole tablet bid twice a week once hematopoiesis has been restored. Alternatively, atovaquone (Mepron; 750mg bid) has been used and is continued for 2 to 3 months post-autologous transplant.

Prevention of herpes zoster in the absence of prophylaxis

- Approximately 40% of patients will develop herpes zoster infection (either dermatomal or disseminated), which is often treated with oral or IV acyclovir. A patient may complain of severe localized pain for several days before the rash develops. The use of valacyclovir (Valtrex) for 1 year after BMT can reduce or delay the risk of reactivation of herpes zoster after allogeneic BMT.

Bacterial prophylaxis

- Although many patients with chronic GVHD following allogeneic transplantation develop an accompanying severe immunodeficiency syndrome that leaves them susceptible to infection with encapsulated bacteria, primarily in the sinuses and lungs, this is generally not the case in patients undergoing autologous transplant.

CMV infection

- Historically, CMV interstitial pneumonia has been responsible for approximately 15 to 20% of patient deaths following allogeneic BMT, but is distinctly rare after autologous transplant. Thus, patients do not require screening or prophylaxis for this virus after autologous transplant.

Growth factors

Growth factors have found their most significant use in the acceleration of hematopoietic recovery after autologous reinfusion of stem cells. Clinical trials in allogeneic transplantation have not shown an advantage to their use, probably due to the immunosuppressive medications such as methotrexate used to prevent GVHD.

Studies do support the use of G-CSF or granulocyte-macrophage colony-stimulating factor (GM-CSF; sargramostim [Leukine, Prokine]) after autologous hematopoietic cell transplantation, although the impact of these growth factors on acceleration of hematopoietic recovery, beyond that achieved with the use of primed autologous stem cells, is not clear.

Erythropoietic agents

Epoetin alfa (Epogen, Procrit) or darbepoetin alfa (Aranesp) is sometimes used effectively in patients who have persistent anemia after transplantation.

Management of relapse

Patients who develop myelodysplasia after autologous transplantation (7 to 10%) can often be successfully treated with reduced-intensity allogeneic transplant (related or unrelated donor) to restore normal hematopoiesis and cure the myelodysplastic syndrome.

What should you tell the patient and the family about prognosis?

What are the long-term problems following autologous transplant?

For patients undergoing autologous stem cell transplantation, the major long-term problem is the risk of relapse and myelodysplasia, but changes in libido, sexual dysfunction, and infertility also should be addressed to help patients achieve good long-term quality of life.

Patients undergoing allogeneic transplantation have similar long term issues but also have major long term effects related to chronic GVHD and the complications related to immunosuppression, especially infection.

In addition, patients undergoing either allogeneic or autologous transplantation are at higher risk for second malignancies, and, thus, aggressive screening studies should be part of the care of all long-term survivors of transplantation.

Second malignancy after HCT

Patients undergoing transplantation are at risk for developing a second cancer. For those undergoing autologous transplantation, particularly for treatment of lymphoma and Hodgkin lymphoma, the most common cancer is myelodysplasia/AML, which occurs in up to 10% of patients, usually within 3 to 7 years after transplantation.

Risk factors for the development of myelodysplasia/AML after transplantation include the number of prior chemotherapy and radiation therapy treatments, specific drugs such as alkylating agents or topoisomerase inhibitors, difficulty in mobilizing stem cells, persistent cytopenias after transplantation, and use of TBI in the transplant preparative regimen. All patients should undergo cytogenetic screening of the marrow prior to stem cell collection and should be followed for this complication after recovery from transplantation.

Patients undergoing either autologous or allogeneic transplantation are also at risk for the development of solid tumors up to 20 years after transplantation. The risk is greater in patients receiving an allogeneic transplant. The most common tumors are related to the skin, but both common (breast, lung, and colon) and less common (sarcoma) tumors have been seen. As part of their long-term follow-up, all patients require screening for this complication to diagnose the cancer in its earliest stage.

“What if” scenarios.

N/A

Pathophysiology

N/A

What other clinical manifestations may help me to diagnose autologous hematopoietic cell transplantation?

N/A

What other additional laboratory studies may be ordered?

After transplantation, depending upon the disease, patients should have a radiographic and marrow examination to restage the patient and determine whether a remission has been achieved, and plans made for post-transplant treatment and follow-up.

[Good summary of the role of autologous transplant in managing patients with relapsed Hodgkin disease.]

Mounier, N, Canals, C, Gisselbrecht, C. "High-dose therapy and autologous stem cell transplantation in first relapse for diffuse large B cell lymphoma in the Rituximab era: An analysis based on data from the European Blood and Marrow Transplantation Registry". Biol Blood Marrow Transplant.

[Important analysis showing the changing benefit of transplant in patients with relapsed disease in the era of Rituxan, suggesting that the disease is harder to eradicate when patients have relapsed after Rituxan-based treatment.]

[The table included in this chapter lists the short term toxicities, usually observed within days to weeks of exposure, and requiring medical management during the initial phase of transplant. The long term toxicities are related to late effects from the regimen on organ function months to years after treatment, and require monitoring as part of the patient’s long term follow-up care.]